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THE EFFECT OF INHALED BUDESONIDE AND FORMOTEROL ON

BRONCHIAL REMODELING IN YOUNG ASTHMATICS

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Introduction• Asthma is a chronic disease, which may cause remodeling

of the airways. The effect of treatment on the reversibility of remodeling is not clear.

• Most of the studies have been conducted in patients with stable disease and the findings may underestimate pathological changes during exacerbations.

• Another difficulty is in following up the structural and histopathological changes overtime in patients using a standard treatment regiment.

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Introduction

• Prevention and/or reversing the structural changes, namely remodeling of the airways, may be the most important step in avoiding the irreversible component of impaired lung function.

• The aim of this study was to determine the effects of therapeutic administration of inhaled budesonide plus formeterol on the structural changes in the bronchi and basement membrane thickness, which are important components of airway remodeling, by means of high-resolution computerized tomography and bronchial biopsy examinations. We also looked for the relation of gross structural changes with BMT.

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Methods

• Thirty-six male patients with mild-to-moderate persistent asthma (age range was 20-31) were given a 3 months of inhaled formoterol and budesonide treatment and bronchial diameter (BD) and bronchial wall thickness (BWT), measured by high resolution computerized tomography, and basement membrane thickness (BMT), assessed in bronchoscopic biopsy specimens, were compared to pretreatment findings.

• Twenty-two age-matching male controls were also enrolled.

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Methods• The thickness of basament membrane was measured with light

microscopy (x 400 magnification) from the line of the end of the epithelial layer to the outer end of the lamina reticularis. To do this, consecutive 3 sections were examined and three measurements were done, at 100 µm intervals, in each section and the mean of 9 measurements was recorded

• Measurements of bronchial dimensions were performed by computer with the use of a dedicated software (Irix Version 6.5 and 3-D Virtuoso V.A. 3.1, Slicon graphics O.R., Mountain View, U.S.A.). With this method, images were enlarged as 5 times and measurements were done digitally.

• A semiquantitative scoring system was used to grade the size of infiltrates, whereby +5 signified a large (>3 cells deep) widespread infiltrate around the majority of vessels and bronchioles, and +1 signifies a small number of inflammatory foci

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Results

• BD values of patients were significantly smaller but BWT and BMT were greater than controls. After 3 months, BWT and BMT of the subsegmental airways were significantly decreased and BD was increased. There was a prominent eosinophilic and lymphocytic infiltration in the bronchial mucosa of asthmatics, and the eosinophilic infiltration significantly improved with treatment. Both serum total IgE and eosinophil counts were related to eosinophilic infiltration scores in the biopsy samples (r = 0.494 and r = 0.463, respectively). FEV1 was correlated to the diameters of segmental and subsegmental

airways (r = 0.491 and r = 0.265, respectively) and negatively correlated with airway wall thickness of subsegmental airways (r = -0.293) and with the BMT of both segmental and subsegmental airways (r = -0.597 and r = -0.590, respectively).

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 Table I: Changes in some clinical parameters with treatment.

  Before Treatment After Treatment P Value

Total IgE (IU/mL) 551.28 ± 581.92 385.34 ± 492.84 0.024

Eosinophil Count (cells/mL)

198.80 ± 88.90 153.57 ± 34.71 0.022

FEV1 (% predicted) 70.72 ± 7.37 75.97 ± 6.85 0.0001

FVC (% predicted) 71.86 ± 10.41 76.75 ± 7.90 0.0001

FEF (% predicted) 59.16 ± 14.79 66.44 ± 14.51 0.003

 

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Parameter (mean of controls) Before Treatment

After Treatment

p Value

Segmental Airways

Mean T (1.38 ± 0.13) 1.39 ± 0.24 1.36 ± 0.26 NS

Mean D (3.56 ± 0.60) 3.09 ± 0.90 3.06 ± 0.86 NS

Mean BMT (5.47 ± 1.74) 10.05 ± 2.62 9.41 ± 2.36 0.083

Eosinophil infiltration score* (1.17 ± 0.39) 2.00 ± 1.06 1.33 ± 0.61 0.003

Lymphocyte infiltration score* (1.19 ± 0.40) 1.41 ± 0.64 1.22 ± 0.42 0.071

Subsegmental Airways

Mean T (0.89 ± 0.19) 1.03 ± 0.21 0.86 ± 0.23 < 0.0001

Mean D (1.63 ± 0.28) 1.45 ± 0.39 1.62 ± 0.32 < 0.0001

Mean BMT (4.90 ± 1.37) 8.57 ± 1.70 7.88 ± 1.76 0.017

Eosinophil infiltration score* (1.16 ± 0.38) 2.06 ± 1.22 1.20 ± 0.41 0.004

Lymphocyte infiltration score* (1.14 ± 0.35) 1.52 ± 0.81 1.33 ± 0.58 0.09

T = bronchial wall thickness measured by HRCT in milimeters; D = bronchial diameter measured by HRCT in milimeters; BMT = basement membrane thickness measured histopathologically in m; (*) described in the methods section.

Table II: Comparison of gross structural and histopathological changes before and after treatment.

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Sample image of basement membrane from a healthy control.

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Sample image of basement membrane from an asthma patient (x200).

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Sample image of basement membrane from an asthma patient.

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Demonstration of the bronchial thickness in an asthma patient (A) and a healthy cotrol (B).

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Asthma (A) and control caes (B) cross-sectional appearance of bronchi with HRCT.

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Discussion• BMT, assessed by endobronchial biopsy, was correlated with the percentage

of smooth muscle, submucosal mucous gland, and with inner wall area in large cartilaginous airways and with inner wall area and area of smooth muscle in small cartilaginous airways

• HRCT findings accurately reflect the anatomic and physiologic changes in the airways and lung parenchymal tissues of patients with asthma

• Epithelial damage and basement membrane thickening were also shown in mild asthma

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Discussion• Some previous studies suggested that increased bronchial thickness is an irreversible feature of asthma• There is evidence to suggest that many of the inflammatory cells remain elevated despite treatment with

corticosteroids • Paganin et al. considered bronchial wall thickening in asthmatic patients as an irreversible structural

abnormality • Ward et al evaluated the effects of up to 12 months treatment with high dose (1.5 mg/day) fluticasone

propionate. Following 3 months of treatment, in the biopsy samples, inflammatory cell counts fell significantly, with no further effect on inflammation with up to 12 months treatment.

• Roche WR. Fibroblasts and asthma. Clin Exp Allergy 1991 Sep;21(5):545-8.• Paganin F et al. Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med

1996; 153: 110-114. • Ward C, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 2002; 57:

309-316. • Louis R, et al. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161: 9-16.

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Discussion• Airway structural abnormalities were associated with the severity of asthma and these abnormalities were, at

least partially, reversible after the successful control of asthma. • Therapeutic administration of budesonide decreased peribronchiolar extracellular matrix deposition, reduced

inflammatory mediator production and modulated transforming growth factor beta signaling pathways, which in turn ameliorated allergen-induced airway remodeling

• Use of low doses of inhaled corticosteroids for 4 weeks resulted in the resolution of eosinophilic infiltration, and down regulation of remodeling markers like metalloproteinase-9 and tissue inhibitor metalloproteinase-1 in persistent-mild asthma

• Sont et al. conducted a prospective, randomized, single-blind trial with a 2 years follow-up and found that vigorous treatment with corticosteroids resulted in reduced BMT

• Lee YM, et al. High resolution CT findings in patients with near-fatal asthma. Comparison of patients with mild-to-severe asthma and normal control subjects and changes in airway abnormalities following steroid treatment. Chest 2004; 126: 1840-1848.

• McMillan SJ, et al. Therapeutic administration of budesonide ameliorates allergen-induced airway remodeling. Clin Exp Allergy 2005; 35: 388-396.

• Vignola AM, et al. Effects of low doses of inhaled fluticasone propionate on inflammation and remodeling in persistent-mild asthma. Allergy 2005; 60: 1511-1517.

• Sont JK, et al. Clinical control and histopathologic outcome of asthma when using airway hyperesponsiveness as an additional guideline to long-term treatment. Am J Respir Crit Care Med 1999; 159: 1043-1051.

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Conclusion• We suggest that treatment with inhaled formoterol and budesonide, may

prevent and even reverse the increased BMT and BWT as part of remodeling in patients with asthma.

• Considering all previous reports regarding this issue, we speculate that the reversibility of bronchial wall thickening probably depends on the underlying pathologic features. It appears to be reversible when submucosal inflammation or edema predominate, and irreversible when the airways are remodeled extensively.

• However, after 3-month treatment of inhaled budesonide plus formeterol, along with other control measures, final situation of airways is highly likely to represent structural changes resistive to treatment.